This study is designed to test the hypothesis that enhanced immune responses to HIV VLPs can be elicited by co-administration of formalin-inactivated influenza virus. We recently found that formalin-inactivated influenza PR8 virus induced antiviral IgM and IgG responses in the absence of CD4+ T cells. The immunized CD4-deficient mice were also found to be completely protected against challenge with live, pathogenic influenza virus. We hypothesize that specific components in influenza virus may play an important role as an adjuvant in inducing immune responses to other weakly antigenic immunogens such as HIV Env even in the absence of CD4+ T cells. Influenza virus particles were reported to bind rapidly to other viruses such as Vesicular stomatitis, Sindbis, or Rauscher murine leukemia virus particles, forming mixed aggregates. Influenza virus binds specifically to neuraminic acid-containing receptors at the surface of other viral particles. We will test the hypothesis that immunization with mixtures of HIV virus-like particles (VLPs) and influenza virus or with phenotypically mixed HIV/influenza VLPs containing influenza HA components may enhance the immune responses induced by HIV VLPs alone. Since one of the characteristics of HIV infected patients is CD4+ T cell depletion, this approach is especially attractive in developing a promising therapeutic HIV vaccine to enhance immune responses in AIDS patients. In this study, we will first determine if formalin-inactivated influenza virus enhances immune responses elicited by HIV VLPs. We will mix HIV VLPs with formalin-inactivated influenza PR8 virus and use them to determine whether enhanced antibody responses are induced in the groups, administered a mixture of HIV VLPs and inactivated influenza virus versus immunization with HIV VLPs alone. We will also compare immune responses induced by the phenotypically mixed HIV/influenza VLPs with HIV VLPS with respect to HIV neutralizing antibody production and cytokine profiles in HIV specific T cells. We will be especially interested in testing in CD4+ T cell knock-out mice if such immunization can also induce antibody responses to HIV and whether HIV specific neutralizing antibody responses will also be induced.